Erythrocyte aging links hypocalcemia to impaired flow dynamics and oxygen transport through volume dysregulation
- 1National University of Singapore Department of Biomedical Engineering
Abstract
Red blood cells (RBCs) maintain their corpuscular volume through mechanotransducive ion-mediated processes in response to circulatory shear stress. However, with age, RBCs accumulate oxidative damage and undergo alterations in protein function, glucose metabolism and ion transport, raising fundamental questions about how volume homeostasis is preserved under mechanical load. Here, we investigated the differential responses of younger (YRBCs) and older RBCs (ORBCs) to fluid shear stress, with a focus on calcium-dependent regulation. We found that ORBCs exhibited a striking dependence on extracellular calcium to maintain volume stability. In calcium-depleted conditions, only ORBCs underwent pronounced post-shear swelling, with recovery only partially restored by ATP-dependent mechanisms. In contrast, calcium preserved volume homeostasis, identifying calcium-sensitive pathways as key compensatory regulators in metabolically compromised ORBCs. Notably, metabolically deficient YRBCs recapitulated the ORBC swelling phenotype, supporting a shift from ATP to calcium-dependent regulation with age. More importantly, shear-induced swelling impaired flow behaviour and oxygen delivery in ORBCs, linking defective volume control to microcirculatory dysfunction. Together, these findings potentially established calcium-dependent volume regulation as a critical adaptive mechanism in ageing RBCs and reveal a previously unrecognized hematological link to vascular dysfunction in hypocalcemia.
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BibTeX
@misc{lim2026erythrocyte,
title = {{Erythrocyte aging links hypocalcemia to impaired flow dynamics and oxygen transport through volume dysregulation}},
author = {J. Lim and J. K. S. Tan and Y. Yuan and E. S. A. Chen and Y. Song and S. L. Tien and H. L. Leo and S. Kim},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.26.762074},
url = {https://www.biorxiv.org/content/10.64898/2026.10.26.762074v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Erythrocyte aging links hypocalcemia to impaired flow dynamics and oxygen transport through volume dysregulation
AU - J. Lim
AU - J. K. S. Tan
AU - Y. Yuan
AU - E. S. A. Chen
AU - Y. Song
AU - S. L. Tien
AU - H. L. Leo
AU - S. Kim
PY - 2026
DA - 2026/10/26
PB - bioRxiv
DO - 10.64898/2026.10.26.762074
UR - https://www.biorxiv.org/content/10.64898/2026.10.26.762074v1
AB - Red blood cells (RBCs) maintain their corpuscular volume through mechanotransducive ion-mediated processes in response to circulatory shear stress. However, with age, RBCs accumulate oxidative damage and undergo alterations in protein function, glucose metabolism and ion transport, raising fundamental questions about how volume homeostasis is preserved under mechanical load. Here, we investigated the differential responses of younger (YRBCs) and older RBCs (ORBCs) to fluid shear stress, with a focus on calcium-dependent regulation. We found that ORBCs exhibited a striking dependence on extracellular calcium to maintain volume stability. In calcium-depleted conditions, only ORBCs underwent pronounced post-shear swelling, with recovery only partially restored by ATP-dependent mechanisms. In contrast, calcium preserved volume homeostasis, identifying calcium-sensitive pathways as key compensatory regulators in metabolically compromised ORBCs. Notably, metabolically deficient YRBCs recapitulated the ORBC swelling phenotype, supporting a shift from ATP to calcium-dependent regulation with age. More importantly, shear-induced swelling impaired flow behaviour and oxygen delivery in ORBCs, linking defective volume control to microcirculatory dysfunction. Together, these findings potentially established calcium-dependent volume regulation as a critical adaptive mechanism in ageing RBCs and reveal a previously unrecognized hematological link to vascular dysfunction in hypocalcemia.
ER -